RESEARCH ARTICLE Open Access

Management of anticoagulation andantiplatelet therapy in patients withprimary membranous nephropathyHonghong Zou†, Yebei Li† and Gaosi Xu*

Abstract

Background: It has been recognized that primary membranous nephropathy (MN) is related to an increased riskfor thromboembolic complications. However, the current evidence supporting prophylactic and therapeuticanticoagulation is too weak to better meet the clinical needs of this patient population. The present reviewprovides some suggestions to guide the decision on anticoagulant management in primary MN patients with ahigh risk of thrombosis or with thromboembolic complication.

Materials and methods: We extracted relevant studies by searching the published literature using the CochraneLibrary, Medline, PubMed and Web of Science from March 1968 to March 2018. Eligible publications includedguidelines, reviews, case reports, and clinical trial studies that concerned the rational management ofanticoagulation therapy in the primary MN population. The evidence was thematically synthesized to contextualizeimplementation issues.

Results: It was helpful for clinicians to make a decision for personalized prophylactic aspirin or warfarin in primaryMN patients when serum albumin was < 3.2 g/dl to prevent arterial and venous thromboembolic events (VTEs). Thetreatment regimen for thromboembolic complications (VTEs, acute coronary syndrome and ischemic stroke) inprimary MN was almost similar to that for the general population with thromboembolic events. It is noteworthythat patients should continue the previous primary MN treatment protocol during the entire treatment period untilthey achieve remission, the protocol is complete and the underlying diseases resolve.

Conclusion: The utility of prophylactic aspirin or warfarin may have clinical benefits for the primary prevention ofthromboembolic events in primary MN with hypoalbuminemia. It is necessary to perform large randomizedcontrolled trials and to formulate relevant guidelines to support the present review.

Keywords: Idiopathic membranous nephropathy, Thromboembolic complications, Anticoagulation, Review

BackgroundPrimary membranous nephropathy (MN) is one of theleading causes of nephrotic syndrome (NS) in adults [1].The aims of therapy in primary MN have mainly focusedon the prevention of end-stage renal disease (ESRD),which usually occurs after several years, whereas othercomplications of primary MN may occur much earlier inthe course of the disease [2]. Venous thromboembolicevents (VTEs), including deep venous thrombosis

(DVT), renal vein thrombosis (RVT) and pulmonaryembolism (PE), are recognized as early complications ofprimary MN that carry significant morbidity and mortal-ity [3]. In particular, hypoalbuminemia is the mostsignificant independent indicator of VTE risk [4]. Alongwith VTEs, high absolute risks of arterial thrombo-embolic events (ATEs) were remarkably elevated withinthe first 6 months after presentation. Severe proteinuria,estimated glomerular filtration rate and smoking werepredictors of ATEs [5–7]. The primary cardiovascularevents (CVEs) included acute coronary syndrome (ACS)and ischemic stroke (IS). It was reported in a Chinesestudy that 36% of primary MN patients had a VTE, 33%

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

* Correspondence: gaosixu@163.com†Honghong Zou and Yebei Li contributed equally to this work.Department of Nephrology, the Second Affiliated Hospital of NanchangUniversity, 330006; No. 1, Minde Road, Donghu District,, Nanchang, People’sRepublic of China

Zou et al. BMC Nephrology (2019) 20:442 https://doi.org/10.1186/s12882-019-1637-y

had an RVT and 17% had a PE [8]. Recent research hasprovided novel data on the incidence of CVEs in primaryMN [9]. The morbidity of CVEs was 4.4, 5.4, 8.2, and8.8% at 1, 2, 3, and 5 years, respectively, in a primaryMN cohort. In addition, they found that the incidence ofCVEs was at least as high as that of ESRD early in thecourse of the disease. Therefore, a reduction in CVEsshould be considered as a focus of intervention and as atherapeutic outcome measure in primary MN.Thus, it is extremely important to implement mea-

sures to prevent thromboembolic events as part of thedaily support care for primary MN patients with hypoal-buminemia. Unfortunately, the current evidence of the2012 KDIGO supporting prophylactic and therapeuticanticoagulation is too weak to better meet the clinicalneeds of this patient population, given the need to care-fully manage anticoagulants and antiplatelet agents, andto tailor the therapeutic regime to an individual’s risks ofthromboembolic events and hemorrhage, we have con-ducted the present review to provide some suggestionsto guide the decision on anticoagulant management inprimary MN with a high risk of thrombosis or withthromboembolic complications.

MethodsWe extracted relevant studies by searching the publishedliterature using the Cochrane Library, Medline, PubMedand Web of Science from March 1968 to March 2018.The PRISMA Extension Checklist for Scoping Reviews(PRISMA-ScR) was attached to make sure the presentreview have included all important standard elements(PRISMA-ScR-Checklist in Supplementary Material).The publications with no title or no abstract and thosenot in English were excluded. The overall results wereanalyzed after the first screening to present an overviewof the existing literature in management of anticoagula-tion in patients with primary MN. Subsequently, wefocused on the literature presenting original research toidentify the use of prophylactic and therapeutic anticoa-gulation in primary MN patients with high risks ofthrombosis or with thromboembolic complications inthe existing research. However, the studies surroundingthe use of prophylactic and therapeutic anticoagulationin patients with primary MN were relatively limited. Weexpanded the scope of the search and studies wereincluded regardless of small sample size. In addition,references from relevant articles were examined for add-itional content not found during the initial search.The predefined key search terms included MN,

membranous glomerulonephritis, NS, prophylacticanticoagulation, anticoagulation, antiplatelet therapy,warfarin, heparin, unfractionated heparin (UFH), lowmolecular weight heparin (LMWH) and direct oralanticoagulant (DOAC), thromboembolic complication,

thromboembolic disease, thrombosis, thromboembolism,thrombotic events, cardiovascular events, venousthromboembolic event, deep venous thrombosis, renalvein thrombosis, pulmonary embolism, arterial thrombo-embolic event, acute coronary syndrome, and ischemicstroke.

Pathogenesis of thrombogenesis in primary MNAt present, the pathogenesis of thrombogenesis in NS isnot absolutely clear, but it seems to be multifactorial.Several mechanisms that promote thrombosis in NShave been identified. First, an alteration in plasma levelsof fibrinolysis and coagulation, along with the urinaryloss of proteins, can lead to lower levels of proteins suchas antithrombin, protein C and protein S [10, 11]. Thedisease-specific risk of VTE is dependent on the levels ofproteinuria and serum albumin, as well as cancerhistory. Second, the risk of an ATE is attributed to in-creased platelet activation and aggregation [12]. Thereare of course other factors that can predispose tothromboembolism such as hyperviscosity, hyperlipid-emia, previous thromboembolic episodes, and steroidtherapy itself, which is commonly used in the treatmentof NS; steroid therapy can cause hypercoagulability andprovoke thrombosis [13].

Results: prevention of thrombogenesis and theanticoagulant management of primary MNThe risk of thromboembolic events is particularly highin primary MN when compared with other pathologicaltypes of NS [14], and most of the patients remainasymptomatic [8]. Therefore, it seems attractive to con-sider the prophylactic use of anticoagulants or antiplate-let agents to prevent VTEs and ATEs in primary MNpatients with high thromboembolic risk. Moreover, therational management of therapeutic anticoagulation andantiplatelet agents in primary MN patients withthromboembolic complications may reduce the recur-rence risk of CVEs.

Prophylactic anticoagulation for primary MNEvidence has shown that low serum albumin is a strongindependent risk factor for VTEs in primary MN [4, 15].A retrospective study indicated that the increasing riskwas proportionately associated with declining albuminlevels. Each 1.0-g/dl decrease in albumin level was asso-ciated with a 2.13-fold increased risk of VTE. Thethreshold albumin level identified for the overall risk ofVTEs was 2.8 g/dl. In other words, a serum albuminlevel < 2.8 g/dl meant a high risk of a VTE [4]. In view ofthe high risk of thromboembolic complications in pri-mary MN, anticoagulation was warranted in patientswho initially presented with thrombotic events [16].

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However, controversy exists about the use of prophylac-tic anticoagulation therapy in primary MN.The 2012 KDIGO suggests that prophylactic oral

warfarin can be considered in primary MN patients onceserum albumin is < 2.5 g/dl and there are additional risksfor thrombosis, whereas some physicians think thatprophylactic anticoagulation should be initiated earlier.Evidence suggests that aspirin has a therapeutic benefitfor the primary prevention of VTEs and the recurrenceof VTEs and results in a significant reduction in the rateof major vascular events with no apparent increase inthe risk of major bleeding [17, 18]. As the pathogenesisof NS was associated with platelet hyperactivity, someinvestigators advocated that primary MN patients couldbe administered antiplatelet agents such as aspirin forthe primary prevention of thrombotic events at an earlystage of disease [19, 20].The benefits of anticoagulation in preventing VTEs

must be weighed against the risk of hemorrhage compli-cations in individual patients. Lee et al. constructed aMarkov-based decision analysis model to estimate thepossibility of benefit based on an individual’s bleedingrisk profile, serum albumin level, and acceptable benefit-to-risk ratio (http://www.med.unc.edu/gntools/) [21].They estimated that 4.5 VTEs would be prevented at thecost of one major bleed during 2 years of therapy withprophylactic anticoagulation (benefit-to-risk ratio = 4.5:1) in patients with a low bleeding risk [Anticoagulationand Risk Factors in Atrial Fibrillation risk (ATRIA) score0 ~ 3 out of 10] and serum albumin < 3.0 g/dl [22]. How-ever, these estimates were based on a retrospective co-hort study with relatively small sample sizes. Therefore,it may not be possible to assess the generalizability/ex-ternal validity of these estimates.Owing to the 0.1% risk of a major bleeding complica-

tion with aspirin, the risk is deemed too high to balancethe benefit of a 25% risk reduction in the general popu-lation with a baseline ATE risk of 5 per 1000 patient-years (py) [23]. In other words, a benefit-risk-ratio of 4:1 represents an absolute ATE risk of 20 per 1000 py ina population [20]. If we accept a benefit-risk-ratio of 4:1, prophylactic therapy seems acceptable in this popula-tion. Hofstra et al. suggested that primary MN patientsmight not need to receive prophylactic anticoagulationwhen serum albumin is > 3.2 g/dl [20]. For patients witha serum albumin of 2.5 ~ 3.2 g/dl, after the evaluationof the ATE risk (https://www.cvdriskchecksecure.com/FraminghamRiskScore.aspx), the researchers did notfavor prophylactic anticoagulation if the ATE risk was< 20/1000 py. Prophylactic aspirin therapy seemedacceptable if the ATE risk was ≥20/1000 py. Theybelieved that the utility of aspirin had clinical benefitsfor primary prevention of ATEs in this patientpopulation [20, 21].

As the HAS-BLED (hypertension, abnormal renal/liverfunction, stroke, bleeding history or predisposition, labileinternational normalized ratio, elderly, drugs/alcohol)bleeding risk score is more predictive of bleeding (cere-bral) than the ATRIA score [24], in our own opinion,once serum albumin is < 2.5 g/dl, prophylactic warfarincan be considered in primary MN patients with a HAS-BLED risk score < 3 [25, 26]. In contrast, we suggest thatprophylactic aspirin can be given to patients with highbleeding risk (HAS-BLED risk score ≥ 3, 20, 21]. A thera-peutic target of the international normalized ratio (INR)is in the range of 2.0 ~ 3.0. Figure 1 guided the decisionon the primary prevention of VTEs and ATEs in primaryMN patients.In view of the facts that aspirin does not appear to in-

crease the risk of major bleeding and the pathogenesis ofNS is associated with platelet hyperactivity, we are moreinclined to implement aspirin as a primary prophylacticanticoagulant for MN patients with a risk of ATEs orVTEs at an early stage of disease. The time of endinganticoagulant therapy should be determined accordingto relevant indicators such as the levels of proteinuriaand serum albumin and the INR. Notably, given thatproteinuria may reduce and the level of serum albuminmay rise in patients with the treatment of primary MNduring the course of disease, the need for any anticoagu-lation requires constant monitoring. Provided that thereis a strong indication that requires anticoagulant therapyin addition to that for primary MN, the patient mighthave lifelong anticoagulation therapy.

Primary MN with complications of VTEsVTEs include DVT and PE, which are the same kind ofdiseases with two different clinical manifestations and attwo different stages. Once the diagnosis of acute DVT(provoked and unprovoked by VTEs) is established3 months of anticoagulation therapy are the best optionfor patients, especially in proximal DVT patients, pa-tients with a high recurrence risk of isolated distal DVT,as well as patients with DVT and PE [27, 28].In patients with DVT not provoked by surgery or can-

cer, DVT treatment is generally composed of three phases.In the initial period of treatment (5 ~ 21 days followingdiagnosis), guidelines suggest that patients receive eitherparenteral therapy for 5 ~ 10 days, such as UFH, LMWHor fondaprinux, and bridge with vitamin K antagonists(VKAs) or use high-dose DOACs. The heparin can bestopped until the INR is maintained in the range of 2.0 ~3.0 for 2 days. Then patients are treated with VKAs orDOACs in a period of long-term treatment (first 3 ~ 6months) [28]. Full or lower doses of LMWH treatment for4 ~ 6 weeks or ultrasound surveillance could be effectiveand safe in patients with a low recurrence risk of isolated

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distal DVT, rather than 3 months of anticoagulationtherapy [27–30].The decision to extend anticoagulant treatment (be-

yond the first 3 ~ 6months) is dependent on the patientand physician’s “trade-off” acceptability of bleeding riskand recurrence risk [27, 28, 30]. For patients with mul-tiple VTE episodes, a strong VTE familial history, or ahigh risk of recurrence, once anticoagulation is stopped,the risk of VTE recurrence in the years after a first epi-sode is consistently approximately 30% [31, 32]. Hence,continuing indefinite anticoagulation with the same drugbeing administered is the best option in this patientpopulation during the extended treatment. It is also suit-able for patients with a first-episode unprovoked VTEand with severe presentation but with low to intermedi-ate bleeding risk to continue indefinite anticoagulation[28, 33]. It is not recommended that patients with highbleeding risk received extended treatment. In patientswith unprovoked proximal DVT and a low risk of recur-rence, provided that veins are recanalized or stable for 1year, the discontinuation of anticoagulation can be con-sidered and has proven to be safe in patients who havebeen repeatedly D-dimer-negative [27, 34]. However, al-though continuous D-dimer measurement could be usedas an indicator to determine whether it is safe to stopanticoagulant therapy in the general population with

VTE, a cross-sectional study suggested that D-dimerlevels might be increased in association with the degreeof proteinuria in NS in the absence of clinically evidentDVT [35]. Therefore, D-dimer levels may not be an in-dependent predictor of the cessation of anticoagulanttherapy in primary MN with VTE.Patients with newly diagnosed proximal DVT who are

not candidates for anticoagulation could have a remov-able vena cava filter placed (if there are no contraindica-tions) [36]. For some patients at high risk of PE with orwithout DVT, reperfusion treatment can be consideredif patients have hypotension. UFH should not be stoppedin reteplase therapy. However, it is usually recom-mended that thrombolytic therapy should not be admin-istered in patients without hypotension [27].Based on the VTE-related guidelines and some litera-

ture, we found that the treatment of VTEs (not provokedby surgery or cancer) in patients with primary MN is al-most similar to that in the general population with VTEs.Of note, D-dimer levels may be affected by proteinuriaand may not be an independent predictor of stoppinganticoagulant therapy in patients with primary MN withVTEs. Moreover, the reduction of proteinuria and the in-crease of serum albumin are also important goals for thetreatment of primary MN with VTEs [37–39]. It is neces-sary to continue the previous steroid therapy or to

Fig. 1 Decision approach for the primary prevention of VTEs and ATEs in primary MN patients. MN: membranous nephropathy; VTE: venousthromboembolic event; ALB: serum albumin; ATE: arterial thromboembolic event; HAS-BLED: hypertension, Abnormal renal/liver function, Stroke,Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol; HAS-BLED score≥ 3: high bleeding risk; Adaptedfrom Hofstra et al. [20] and Lee et al. [21]

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combine it with immunosuppressive agents over the entiretreatment period until the primary MN treatment proto-col is completed. However, there is currently no clinicaltrial data on how long anticoagulation should last in thispatient population. In our own opinion, for primary MNpatients with VTEs, one potential approach is to receiveanticoagulation at least 3 ~ 6months (if there are no con-traindications) until serum albumin levels normalize andpatients achieve remission. If there is a strong indicationfor anticoagulation therapy, such as atrial fibrillation (AF)or multiple VTEs, indefinite anticoagulation therapy isrecommended (unless there is a contraindication). Ofcourse, we believe that a comprehensive risk factor assess-ment is essential, and any anticoagulation therapy needsto be continuously monitored during the entire treatmentperiod. Figure 2 shows the anticoagulant management al-gorithm in primary MN patients diagnosed with a VTE.Apixaban, as a DOAC, provides an effective and safe

regimen for the initial and long-term treatment of DVTand PE compared to conventional therapy (subcutaneousenoxaparin, followed by warfarin) and reduces the riskof recurrent DVT and PE compared to placebo followinginitial therapy [40, 41]. A retrospective cohort study andthe seminal ARISTOTLE trial showed that among thepatients with ESRD and AF on dialysis or those withonly AF, apixaban use may be associated with a lowerrisk of stroke, bleeding and death compared with war-farin [42, 43]. Furthermore, a meta-analysis showed thatmajor bleeding and fatal bleeding were significantlylower in DOAC-treated patients [44]. DOACs were atleast as effective as and possibly safer than parenteraldrug/VKA therapy.Notably, apixaban and rivaroxaban are highly bound

to plasma proteins (87, 90% ~ 95%) in humans, andserum albumin is the main binding component. If thesedrugs are considered for patients with hypoalbuminemia,the protein binding rate is an important consideration inprimary MN [45, 46]. At present, although no pharma-cokinetic study was available and no clinical trial hadbeen performed in primary MN, some case reportsreported the successful use of DOACs for the treatmentof clinically evident thrombosis or thromboprophylaxisin primary MN [46]. Although the literature on DOACuse in NS is limited, the preliminary experience seemspromising. Therefore, we believe that DOACs may beconsidered for anticoagulant therapy in primary MNwith VTEs. Notably, the choice of DOACs ought to beindividualized based on specific patient factors, for in-stance, renal function, and the risk of thrombosis andbleeding.Since most of the DOACs are largely excreted through

the kidneys, the degree of renal impairment is an im-portant factor in determining whether DOACs can beused and in selecting the appropriate doses. Severe renal

impairment in primary MN patients [creatinine clear-ance (CrCl) < 15ml/min] is a contraindication forDOACs. Mild renal impairment (CrCl > 50 ml/min) haslittle effect on DOAC pharmacokinetics. If CrCl isbetween 15 and 50ml/min, discretionary reduction is re-quired [47]. Since limited data are available, it is necessaryto conduct risk stratification and careful follow-up ofthese patients to ensure a net clinical benefit of thrombo-prophylaxis. It is worth noting that DOACs are not suit-able for all individuals with severe kidney disease [48].

Primary MN with complications of ACSThe hypercoagulability associated with NS can result inthe development of an occlusive coronary arterythrombus in absence of atherosclerotic coronary arterydisease [49]. ACS, ST-elevation myocardial infarctionand non-ST-elevation myocardial infarction is not a veryrare complication; sometimes, it can be the first mani-festation in primary MN [49–52]. the accurate diagnosisof the complication is imperative for suitable manage-ment and secondary prevention in primary MN [53].Currently, neither primary MN-related nor ACS-relatedguidelines can provide the recommendations associatedwith the management of anticoagulant and antiplateletagents in primary MN patients with the complication ofACS. The optimal management of the medications isstill under discussion.According to the guidelines, once ACS is diagnosed,

the bleeding risk in addition to the ischemic risk shouldbe carefully evaluated during the acute phase of theACS. It is recommended that the earliest possible drugadministration is dual antiplatelet therapy in the prehos-pital setting. Furthermore, ACEIs/ARBs, statins and β-blockers should be administered as soon as possible afteradmission [54–56]. No matter which type of therapy isapplied (conservative treatment, reperfusion therapywith percutaneous coronary intervention or thrombo-lytic agents, etc.), it is usually recommended to use UFHor enoxaparin or bivalirudin immediately after conserva-tive treatment or reperfusion therapy [57, 58]. The de-tails are as follows: in ST-elevation myocardial infarctionpatients who receive thrombolytic therapy, UFH orenoxaparin should be used around the time of reteplaseor alteplase therapy. For patients with conservative treat-ment or percutaneous coronary intervention, bivalirudinis the better choice than UFH if patients are at a highrisk of bleeding [55]. After hospital discharge, ACEIs/ARBs, statins, β-blockers and low doses of aspirin shouldbe indefinitely continued, and 12 months of P2Y12 re-ceptor antagonist therapy is needed. Stopping P2Y12 re-ceptor antagonist therapy can be considered in patientswith a high risk of bleeding after 6 months. The statinsshould not be stopped blindly and the dosage should not

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be reduced even when low-density lipoprotein choles-terol is lower than 2.07 mmol/L.We analyzed the existing case reports and reviews that

detailed the treatment process and found that, in gen-eral, in primary MN patients with a confirmed diagnosisof ACS, the treatment regimen of ACS was almost simi-lar to that of the general population with ACS. It wasnoteworthy that a majority of primary MN patients withACS continued the previous primary MN treatmentprotocol during the entire treatment period until theyobtained remission (partial or complete remission) and

the protocol was completed [49–52]. Provided that thereis an additional strong indication that requires anti-coagulant therapy, over and above that of their primaryMN with ACS, the patient might have extra lifelonganticoagulation therapy [49]. Since we were reviewingthe treatment options in the existing case reports and re-views, the views we presented might have limitations.The treatment regimen of primary MN patients withACS should be individualized based on specific patientfactors. The medication management of primary MN pa-tients with ACS is shown in Fig. 3.

Fig. 2 Proposed algorithm to guide the decision on anticoagulant management in primary MN patients with VTE. MN: membranousnephropathy; VTE: venous thromboembolic event; DVT: deep venous thrombosis; PE: pulmonary embolism; AC: anticoagulation; m: month; d:days; VKA: vitamin K antagonists; DOAC: direct oral anticoagulant; w: weeks; LMWH: low molecular weight heparin; US: ultrasound surveillance

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Primary MN with complications of ISIS is one of the most severe complications of NS. Thehypercoagulable state may be the main contributing fac-tor of IS in NS [59]. A cohort study showed that ISaccounted for 45% of the ATEs in Chinese patients withprimary MN [7]. IS usually occurs at the initial onset orupon the relapse of primary MN and it lacks specificclinical manifestations. Therefore, early diagnosis and in-tensive treatment are crucial to the prognosis of IS inprimary MN [60].According to the related recommendations, the thera-

peutic strategies for IS in the general population includeendovascular intervention, thrombolysis, antiplatelettherapy and anticoagulation therapy [61]. After the

assessment of risks and benefits by the physician, hep-arin or VKA therapy can be considered in patients witha hypercoagulable state 24 h after thrombolysis or endo-vascular intervention. The discontinuation of the drugscan be considered until the INR is in the range of 2.0 ~3.0. It is usually unnecessary for patients who are not ina hypercoagulable state to receive early anticoagulationtherapy. Recommendations suggest starting aspirin ther-apy 24 h after thrombolysis. One to 3 months of dualantiplatelet therapy is recommended for patients afterendovascular intervention. For patients who are pre-pared to receive conservative treatment, it is generallynot recommended to undergo anticoagulation therapy;they should begin aspirin therapy as soon as possible. If

Fig. 3 Proposed decision-making algorithm of medication in primary MN patients with ACS. MN: membranous nephropathy; ACS: acute coronarysyndrome; STEMI: ST-elevation myocardial infarction; NSTE: non ST-elevation; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensinreceptor blocker; PCI: percutaneous coronary intervention; AC: anticoagulation; UFH: unfractionated heparin; LRB: low risk of bleeding; HRB: highrisk of bleeding; h: hours; LDL-C: low-density lipoprotein cholesterol

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patients suffer from a slight IS (course of the disease iswithin 24 h and NIHSS score is ≤3), continuing dual an-tiplatelet therapy for 21 days may be an optimal choice.In addition, it is recommended that, for all IS patients,the indefinite use of aspirin or clopidogrel is an accept-able strategy for the secondary prevention of IS [62, 63].However, the evidence for the efficacy and safety of

medication management in primary MN with IS has yetto be determined. We found that in the existing case

reports and reviews, once the diagnosis of IS was estab-lished in primary NM, the treatment for IS was largelysimilar to the therapy for IS in the general population.Simultaneously, patients continued the previous primaryMN treatment protocol until they achieved remissionand the protocol was completed (Fig. 4) [6, 59, 64, 65].According to individuals’ conditions, some patients are

more inclined to receive anticoagulant therapy (paren-teral therapy and then bridge with VKAs) after the

Fig. 4 Authors’ suggestions for medication management in primary MN patients with ischemic stroke. MN: membranous nephropathy; IS:ischemic stroke; AC: anticoagulation; h: hours; m: month; INR: international normalized ratio; UFH: unfractionated heparin; LMWH: low molecularweight heparin; DAPT: dual antiplatelet therapy

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thrombolysis therapy or the endovascular intervention[6, 65]. Since platelet hyperaggregability plays an import-ant role, antiplatelet therapy may be useful in reducingthe risks of thromboembolic disease in primary MN.Some patients are treated with dual antiplatelet agentsauch as aspirin and clopidogrel after IS-related support-ive care [59, 64]. To what extent the use of anticoagu-lants and antiplatelet agents can prevent IS in primaryMN is yet unknown. Further numerous clinical data areneeded to determine the role of anticoagulants and anti-platelet agents in the primary and secondary preventionof IS in primary MN.

DiscussionSummary of evidenceIn this review, we eventually identified 65 primary stud-ies addressing prophylactic and therapeutic anticoagula-tion therapy in primary MN. Our findings revealed apaucity of research focusing specifically on prophylacticor therapeutic anticoagulation in primary MN patientswith a high risk of thrombosis or with thromboemboliccomplication and a limited number of clinical trials inthis area. We found that personalized prophylactic as-pirin or warfarin could be considered to prevent ATEsand VTEs in primary MN patientsvwith serum albumin< 3.2 g/dl. Moreover, the treatment regimen of thrombo-embolic complications in primary MN patients wassimilar to that in the general population with thrombo-embolic events. Since more evidence indicated thatDOACs provided an effective and safe regimen for anti-coagulant treatment in NS compared to conventionaltherapy, they might be a promising anticoagulant inprimary MN. Last but not least, the patients shouldcontinue the previous primary MN treatment protocolduring the entire treatment period until they achieve re-mission, the protocol is completed and the underlyingdiseases have resolved.

LimitationsThere were some limitations in the present review. Mostof the evidence for prophylactic anticoagulation recom-mendations for primary MN was derived from retro-spective studies. Randomized controlled trials should beconducted to support this evidence. The views on pri-mary MN patients with ACS or IS presented in the re-view were based on the existing reviews, case reports,ACS- and IS-related guidelines, which lacked convincingdirect evidence. The current evidence supportingprophylactic and therapeutic anticoagulation is too weakto better meet the clinical needs in primary MN patients.The optimal, standardized approach has not been clearlyestablished. The issues discussed in the present reviewmight be valuable as a basis for a discussion leading to aconsensus statement by scientific societies or for an

update of guidelines on the management of IMN. Inother words, it is necessary to perform multicenteredrandomized controlled trials to support the presentreview.

ConclusionThe utility of prophylactic aspirin or warfarin may have clin-ical benefits for the primary prevention of thromboembolicevents in primary MN patients with hypoalbuminemia.

AbbreviationsACEI/ARB: angiotensin converting enzyme inhibitor/angiotensin receptorblocker; ACS: acute coronary syndrome; AF: atrial fibrillation; ATE: arterialthromboembolic event; ATRIA: anticoagulation and risk factors in atrialfibrillation; CrCl: creatinine clearance; CVE: cardiovascular event; DOAC: directoral anticoagulant; DVT: deep venous thrombosis; ESRD: end stage renaldisease; HAS-BLED: hypertension, abnormal renal/liver function, stroke,bleeding history or predisposition, labile international normalized ratio,elderly, drugs/alcohol; INR: international normalized ratio; IS: ischemic stroke;LMWH: low molecular weight heparin; MN: membranous nephropathy;NS: nephrotic syndrome; PE: pulmonary embolism; py: patient-years;RVT: renal vein thrombosis; UFH: unfractionated heparin; VKA: vitamin Kantagonists; VTE: venous thromboembolic event

AcknowledgementsNot applicable.

Authors’ contributionsHHZ performed the literature searching, reviewed articles, and wrote themanuscript. YBL reviewed the articles and provided the second views duringthe manuscript preparation. GSX designed and revised the manuscript. Allthe authors read and approved the final version of the manuscript.

FundingThis work was supported by the National Natural Science Foundation ofChina (No.H0517/81560132). The funding body has no role in the design ofthe study, data collection, analysis and neither interpretation of data norwriting of the manuscript.

Availability of data and materialsNot applicable.

Ethics approval and consent to participateNot applicable.

Consent for publicationNot applicable.

Competing interestsThere is no conflict of interest to report here.

Received: 15 May 2019 Accepted: 21 November 2019

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